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Johannes H. M. Merks, MD, PhD; Heval M. Özgen, MD; Jan Koster, PhD; Aeilko H. Zwinderman, PhD; Huib N. Caron, MD, PhD; Raoul C. M. Hennekam, MD, PhD

JAMA. 2008;299(1):61-69.

Context  Constitutional gene defects predispose to cancer in children. Such tumor predisposition syndromes can be recognized by specific patterns of morphological abnormalities.

Objectives  To assess the prevalence of morphological abnormalities in a large cohort of patients with childhood cancer and to identify new tumor predisposition syndromes.

Design, Setting, and Participants  Patients were recruited from Emma Children's Hospital, Academic Medical Center, Amsterdam, the Netherlands, between January 2000 and March 2003. A total of 1073 patients underwent a physical examination directed at 683 morphological abnormalities. The patient cohort consisted of 898 long-term survivors of childhood cancer and 175 newly diagnosed pediatric patients with cancer. The control group consisted of 1007 schoolchildren examined in an identical way. Mean ages of patients and controls were 21.2 and 10.4 years, respectively.

Main Outcome Measures  Prevalence and patterns of morphological abnormalities in patients compared with controls. To prevent age bias, only age-independent abnormalities were used for overall prevalence analysis. Patients younger than 9 years were excluded from the pattern analysis. The sample was restricted to white patients to prevent ethnicity bias.

Results  Morphological abnormalities were significantly more prevalent in pediatric patients with cancer. Major abnormalities were present in 26.8% of patients vs 15.5% of controls (P < .001) and minor anomalies in 65.1% of patients vs 56.2% of controls (P < .001). Three or more minor anomalies were detected in 15.2% of patients vs 8.3% in controls (P < .001). Forty-two patients were diagnosed with an established tumor predisposition syndrome. Multivariate analyses showed 14 morphological abnormalities to occur significantly more often in the patient group. For 2 of these (blepharophimosis and asymmetric lower limbs), we identified statistically significant patterns of co-occurring morphological abnormalities suggestive of new tumor predisposition syndromes. Thirty-four patients fit 1 of the 2 novel tumor predisposition patterns.

Conclusions  Pediatric patients with cancer show a significantly higher prevalence of morphological abnormalities compared with controls. Specific patterns of morphological abnormalities indicate possible unrecognized tumor predisposition syndromes, but validation in an independent sample is needed.

Author Affiliations: Departments of Pediatric Oncology (Drs Merks and Caron) and Pediatrics (Drs Özgen and Hennekam), Emma Children's Hospital, Academic Medical Center, Amsterdam, the Netherlands; Department of Pediatric Psychiatry, Wilhelmina Children's Hospital, University Medical Center, Utrecht, the Netherlands (Dr Özgen); Institute of Child Health, Great Ormond Street Hospital for Children, University College London, London, England (Dr Hennekam); and Departments of Human Genetics (Dr Koster) and Clinical Epidemiology and Biostatistics (Dr Zwinderman), Academic Medical Center, Amsterdam, the Netherlands.

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